Nicotinic acetylcholine receptors (“nAChRs”) are ligand-gated ion channels found in cell plasma membranes in various tissues, including skeletal muscle at the neuromuscular junction, the peripheral nervous system, and the central nervous system. Nicotinic ligands have traditionally been classified as agonists (or partial agonists) that activate channel function, or competitive or noncompetitive antagonists, that block channel function. Ligands such as acetylcholine and nicotine are agonists, which act by binding to and effecting opening of nAChRs, and allowing the influx of cations into a cell to produce an excitatory response. nAChRs can also exist in a desensitized state, in which channel function is blocked in the presence of an agonist. Chronic nicotine exposure is associated with desensitization and inactivation of nAChRs.
nAChRs are potential therapeutic targets for the treatment of central and peripheral nervous system disorders, including neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's disease), age-related or disease-related cognitive impairment, dyskinesias, Tourette's syndrome, schizophrenia, attention-deficit hyperactivity disorder, depression, anxiety, mood disorders, pain, and methamphetamine addiction. In addition, nAChRs are the biological substrate through which nicotine acts in the body. Studies have shown that tobacco use is driven by nicotine addiction, in part because of nicotine's beneficial effects on cerebral functions, such as stabilizing mood and emotion and producing pro-cognitive and pro-attentive effects. Epidemiological studies have shown that people with cognitive or mood disorders are often nicotine dependents, which strongly suggests that nicotine use is a form of self-medication to treat such disorders. Thus, nAChRs are potential targets for treating or preventing nicotine addiction. Moreover, nicotinic acetylcholine receptors in the brain are thought to play a role not only in cholinergic neurotransmission at selected loci, but more globally in the modulation of neurotransmission by other chemical messengers (e.g., dopamine, norepinephrine or serotonin), and therefore, may play a role in central and peripheral nervous system disorders that do not result directly from irregularities in cholinergic neurotransmission.
Nicotinic acetylcholine receptor channels exist as a family of subtypes, and each subtype is composed of a homo- or hetero-pentamer of protein subunits encoded by one of 16 mammalian genes. Each nAChR subtype has a distinctive biophysical, physiological and pharmacological signature. In addition, each nAChR subtype has a unique tissue, regional, cellular and subcellular localization pattern. For example, the predominant nAChR subtype in the central nervous system is the α4β2 subtype, which is composed of α4 and β2 protein subunits that are known to assemble in a 2:3 ratio. The α4β2 nAChR binds nicotine with high affinity.
The discovery of the subunit composition, characteristics and localization patterns of particular nAChR subtypes presents an opportunity in drug discovery for novel compounds that can be administered to treat central and peripheral nervous system disorders, or to aid in smoking cessation, by selectively modulating the activity of particular receptor subtypes found predominantly in the targeted tissues. Subtype-selective drugs also have the potential to reduce side effects, and to be critical tools to help identify and distinguish functions and responses mediated by particular receptor subtypes.
The publication “Neuronal nicotinic acetylcholine receptors as targets for drug discovery,” of Holladay et al. (J. Med. Chem. 40(26):4169-4194 (1997)) describes the characteristics of different nAChR subtypes and discusses the potential development of selective agonists and antagonists of nAChRs.
U.S. Pat. Nos. 5,629,325, 6,127,386 and 6,437,138 and International PCT Publication No. WO 97/46554 to Lin et al. describe 3-pyridyloxymethyl heterocyclic ether compounds useful for controlling chemical synaptic transmission.
International PCT Publication No. WO 2005/000806 A2 describes ligands for nicotinic acetylcholine receptors and methods of making and using them.
U.S. Pat. No. 6,277,855 to Yerxa describes methods of treating dry eye disease with nicotinic acetylcholine receptor agonists.
International PCT Publication Nos. WO 2006/125641 A2 and WO 07/085565 A1 describe methods of using 3-pyridyl derivatives as pesticides.
International PCT Publication No. WO 2008/0132486 to Kozikowski et al. describes ligands for nicotinic acetylcholine receptors, and methods of making and using them.
International PCT Publication No. WO 2008/011484 A2 to Xiao and Kellar describes nicotinic acetylcholine receptor desensitizers and methods of selecting, testing, and using them.
The publication “Synthesis and pharmacological evaluation of some (pyridyl)cyclopropylmethyl amines and their methiodides as nicotinic receptor ligands” of Guandalini et al. (Il Farmaco 57: 487-496 (2001)) describes the synthesis of a number of pyridyl cyclopropylamine compounds and their activities at nicotinic acetylcholine receptors.
The publication “Sazetidine-A is a potent and selective agonist at native and recombinant α4β2 nicotinic acetylcholine receptors” of Zwart et al. (Molecular Pharmacol. 73:1838-1848 (2008)) describes the agonist activity of sazetidine-A at α4β2 nicotinic acetylcholine receptors.
Citation of any reference in this section of the application is not to be construed as an admission that such reference is prior art to the present application.